WO2009114136A2 - Dérivés de fenrétinide et leurs utilisations comme agents thérapeutiques, de diagnostic et d'imagerie - Google Patents

Dérivés de fenrétinide et leurs utilisations comme agents thérapeutiques, de diagnostic et d'imagerie Download PDF

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WO2009114136A2
WO2009114136A2 PCT/US2009/001538 US2009001538W WO2009114136A2 WO 2009114136 A2 WO2009114136 A2 WO 2009114136A2 US 2009001538 W US2009001538 W US 2009001538W WO 2009114136 A2 WO2009114136 A2 WO 2009114136A2
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compound
cancer
fenretinide
hpr
derivatives
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WO2009114136A3 (fr
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Ganjam V. Kalpana
Bhasar C. Das
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Albert Einstein College Of Medicine Of Yeshiva University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1255—Granulates, agglomerates, microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/28—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings

Definitions

  • the present invention relates to synthetic derivatives of Fenretinide (4-HPR) and their uses as therapeutic, diagnostic and imaging agents for cancer and other diseases.
  • 4-HPR N-(4- hydroxyphenyl)retinamide, or Fenretinide
  • 4-HPR is a synthetic retinoid that has potent chemopreventive and antipr liferative effects against many cancers in vitro and in preclinical models, and it does not show appreciable side effects. It exhibits cytotoxicity and in vitro suppresses tumor cell growth at low micromolar concentrations (IC50s) ranging from 1-10 ⁇ M (1).
  • 4-HPR is an FDA approved drug under phase II clinical trials for many cancers including neuroblastomas, currently sponsored by the National Cancer Institute (Ref: 06-C- 0227).
  • Fenretinide has been largely studied as a chemo-preventive agent in carcinogen- induced epithelial tumors in animal models and in patients at risk for breast cancer (2-5).
  • 4HPR has minimal activity; however, in comparision to other retinoids, has low toxicity (2-4).
  • recent results of a fifteen-year follow up studies of Phase III trials of Fenretinide to prevent second breast cancer indicated that it has significant risk reduction in premenopausal women, which is remarkable at younger age, and persists after several years (6).
  • These studies indicate that Fenretinide has promising preventive activity in clinical trials of breast cancer.
  • use of 4HPR has demonstrated prolonged stabilization of disease in pilot clinical studies (7-10).
  • 4HPR induces apoptosis in tumor cell lines in vitro by various mechanisms including: (i) activation of retinoid receptors RAR ⁇ and ⁇ ; (ii) induction of ceramide- dependent cell cytotoxicity that is independent of p53 or caspase-3 function and thus is synergistic with tamoxifen, which in turn is an inhibitor of glucosylceramide synthase; (iii) generation of free radical oxygen species; (iv) increase of NOS expression resulting in increased NO-dependent cell cytotoxicity; and (v) increase of mitochondrial permeability transition (2, 4, 7, 8, 10).
  • 4HPR also induces cell cycle arrest and down modulates the expression or activity of proliferation related targets such as c-myc, telomerase, p34/cdc2 and Cyclin (10-21). These effects correlate with the induction of phosphorylation of Rb, cell cycle arrest and subsequent induction of apoptosis.
  • 4-HPR as a therapeutic agent for diseases other than cancer: 4-HPR is a retinoid and as such it is likely to interfere with the retinoic acid pathway in the cells and affect the biology of the pathway. Since defects in retinoic acid synthesis, metabolism, and transcriptional regulation of downstream genes by its ability to bind to nuclear receptors (RAR and RXR) are important for growth, development, behaviour, and disease pathways (31-37), retinoic acid metabolism inhibitors are widely used as therapeutic agents in many diseases (38).
  • RAR and RXR nuclear receptors
  • Fenretinide is a synthetic retinoid that induces apoptosis in cancer cells as opposed to retinoic acid and other retinoids that induce differentiation (4). Because of this reason, and because of its low toxicity and effect on many different pathways including ceramide biosyntesis, free radical oxygen, and NOS, Fenretinide has been widely investigated as a preventive or therapeutic agent in many diseases. In addition to cancer, several preclinical studies have suggested activity of this compound against an array of diseases including but not limited to diabetes, AIDS, Alzheimer's Disease, cystic fibrosis, allergic encephalomyelitis, and ichthyosis (4, 39-61).
  • 4-HPR analogues in inducing cytotoxicity 4-HPR is one of the most widely investigated synthetic retinoids for cancer prevention, especially for breast cancer.
  • Pharmacological studies in human clinical trials of breast cancer patients have revealed accumulation of plasma concentration of 4-HPR at 1 ⁇ M levels with administration of 200 mg/day (MTD) of 4-HPR (3). It is possible that a molar concentration higher than currently attainable within the tumors may be required to achieve desired cytocidal effect with 4-HPR in other human cancers. Additional studies have indicated that in vitro activity of Fenretinide does not match a correspondent efficacy in vivo, indicating a need for further improvement of the drug.
  • the invention provides a compound having the formula:
  • R is OH; wherein Ri, R 2 and R 3 are independently H, Br, Cl, I, F, alkyl, aryl, OH, NO 2 , NHR 4 , OR 4 or heterocyclic, where R 4 is alkyl, aryl or heterocyclic, and where at least one of Ri, R 2 and R 3 is not H; or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound having the formula:
  • R is OH; wherein Ri, R 2 and R 3 are independently H, Br, Cl, I, F, alkyl, aryl, OH, NO 2 , NHR 4 , OR 4 or heterocyclic, where R 4 is alkyl, aryl or heterocyclic; or a pharmaceutically acceptable salt thereof.
  • the invention also provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or diluent.
  • the invention further provides a method of treating a subject having a cancer comprising administering to the subject a compound of the present invention in an amount and manner effective to treat cancer in the subject.
  • the invention further provides a method of treating a subject having a disease comprising administering to the subject a compound of the present invention in an amount and manner effective to treat the disease in the subject.
  • FIG. 1A-1D Effect of 4HPR derivatives with phenyl group substitutions on survival of rhabdoid tumors cells.
  • MON Il-/- cells were treated with serial dilutions of the 4HPR, ATRA and 4HPR derivatives for three days. Survival assay was carried out as described using MTS assay kit. Percentage of cell survival plotted against concentration of drugs (Mean+/-SEM).
  • Figure 2 Effect of fenretinide peptidomimitic derivatives on the survival of rhabdoid tumor cells in culture. % survival of MON rhabdoid tumor cells treated with fenretinide derivatives, when compared to the vehicle treated control. The data in all the panels represent the average of triplicate experiments, and the standard error is indicated.
  • Figure 3A-3B Induction of cell cycle arrest and apoptosis by halogen derivatives of fenretinide.
  • A Cell cycle profile determined by FACS analysis of MON cells treated with either 5 or lO ⁇ M concentrations of fenretinide and its derivatives for 2 days. Percentage of cells at various stages of cell cycle (Gl, S and G2) is indicated.
  • B B.
  • FIG. 4A-4B Induction of cell cycle arrest and apoptosis by peptidomimetic derivatives of fenretinide.
  • A Cell cycle profile determined by FACS analysis of MON cells treated with either 5 or lO ⁇ M concentrations of fenretinide and its derivatives for 2 days. Percentage of cells at various stages of cell cycle (Gl, S and G2) is indicated.
  • B Percentage of MON cells at SUb-G 1 when exposed for 2 days to fenretinide and its derivatives.
  • the invention provides a compound having the formula: wherein R is OH; wherein Rj, R 2 and R 3 are independently H, Br, Cl, I, F, alkyl, aryl, OH, NO 2 , NHR 4 , OR 4 or heterocyclic, where R 4 is alkyl, aryl or heterocyclic, and where at least one of Ri, R 2 and R 3 is not H; or a pharmaceutically acceptable salt thereof.
  • at least one of Ri, R 2 and R 3 is OH, Br, Cl, I or F; and at least one of Ri, R 2 and R 3 is H.
  • at least one of Ri and R 3 is Br, Cl, I or F.
  • R 3 is I.
  • R 2 is H or OH.
  • Preferred compounds include, but are not limited to, compounds selected from the group consisting of:
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound having the formula:
  • R is OH; wherein R 1 , R 2 and R 3 are independently H, Br, Cl, I, F, alkyl, aryl, OH, NO 2 , NHR 4 , OR 4 or heterocyclic, where R 4 is alkyl, aryl or heterocyclic; or a pharmaceutically acceptable salt thereof.
  • Rj, R 2 and R 3 is OH, Br, Cl, I or F; and at least one of Ri, R 2 and R 3 is H.
  • at least one of Ri and R 3 is Br, Cl, I or F.
  • R 3 is I.
  • R 2 is H or OH.
  • Preferred compounds include, but are not limited to, compounds selected from the group consisting of:
  • the compound is:
  • salts are non-toxic salts derived for example from inorganic or organic acids including, but not limited to, salts derived from hydrochloric, sulfuric, phosphoric, acetic, lactic, fumaric, succinic, tartaric, gluconic, citric, methanesulphonic and p-toluenesulphonic acids.
  • the compounds of the present invention can be radiolabeled.
  • Preferred radiolabels include, but are not limited to, F-18, Cl-34m, Br-75, Br-76, 1-120, 1-122, 1-123, I-
  • the compound of the present invention can be conjugated to a nanoparticle.
  • the nanoparticle is conjugated to the compound at position R, Ri, R 2 or R 3 .
  • the compounds of the present invention have improved efficacy, bioavailability and/or ability to cross the blood-brain barrier compared to N-(4- hydroxyphenyl)retinamide (4-HPR).
  • the invention also provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or diluent.
  • Pharmaceutically acceptable carriers and diluents encompasses any of the standard pharmaceutical carriers or diluents, such as, for example, a sterile isotonic saline, phosphate buffered saline solution, water and emulsions, such as an oil/water or water/oil emulsions.
  • the invention further provides a method of treating a subject having a cancer comprising administering to the subject a compound of the present invention in an amount and manner effective to treat cancer in the subject.
  • Preferred forms of cancer include, but are not limited to, breast cancer, a rhabdoid tumor, a neuroblastoma, ovarian cancer, renal cancer, a malignant glioma and prostrate cancer.
  • the invention further provides a method of treating a subject having a disease comprising administering to the subject a compound of the present invention in an amount and manner effective to treat the disease in the subject.
  • Preferred diseases include, but are not limited to, diabetes, AIDS, Alzheimer's Disease, cystic fibrosis, allergic encephalomyelitis and ichthyosis.
  • the compounds of the present invention can be administered to subjects using routes of administration known in the art.
  • the administration can be systemic or localized to a tumor site.
  • Routes of administration include, but are not limited to, intravenous, intramuscular, intrathecal or subcutaneous injection, oral or rectal administration, and injection into a tumor site.
  • the invention also provides for the use of any of the compounds disclosed herein for treating a subject with cancer or other disease, and for the use of any of the compounds disclosed herein for the preparation of a medicament for treatment of cancer or other disease.
  • the invention further provides pharmaceutical compositions comprising any of the compounds disclosed herein for treatment of cancer or other disease.
  • the invention also provides a method of screening for compounds that inhibit rumor cell growth, the method comprising determining whether or not a compound down modulates Cyclin Dl and/or causes Gl cell cycle arrest, wherein a compound that down modulates Cyclin Dl and/or causes Gl cell cycle arrest is a candidate compound for inhibiting tumor cell growth and wherein a compound that does not down modulate Cyclin
  • Dl and/or cause Gl cell cycle arrest is not a candidate compound for inhibiting tumor cell growth.
  • Peptidomimetic derivatives, nanoparticle conjugates and radio-labeled derivatives and their significance A chemical biology approach was undertaken to synthesize new peptidomimetic and functionalized derivatives of 4-HPR molecules to improve the efficacy, bioavailability and ability to cross the blood-brain barrier. Furthermore, a chemical synthesis approach was undertaken to synthesize radio-conjugates of 4-HRP to facilitate diagnostic, pharmacokinetic studies and to combine chemotherapy with radiotherapy using a single drug.
  • Peptidomimetics in broad terms, refer to molecules bearing identifiable resemblance to peptides that as a ligand of a biological receptor can imitate or inhibit the effect of a natural peptide (68-71). Peptidomimetics are superior to natural or synthetic peptides as therapeutic agents because they: (i) are less susceptible to proteolytic degradation; (ii) are better absorbed through the cell membrane; (iii) are transported across the blood-brain barrier efficiently; and/or (iv) because of their rigidity, exhibit specificity in their interaction with biological molecules. Peptidomimetics are designed by altering the amide bond of a compound and are further modified by cyclization, isostere replacement and changing the scaffold. Compounds that are not necessarily peptides but have amide bonds within their structures can also be modified based on these principles to improve their properties such as efficacy, solubility, bioavailability and/or transport.
  • Nanoscience and nanotechnology refer to research at the atomic, molecular or macromolecular levels, at the length scale of approximately 1 - 100 nanometers.
  • the emerging goal of the nanotechnology is to functionalize inert and biocompatible materials to impart precise biological functions.
  • new materials have been synthesized and tested for diagnostic and therapeutic agents including quantum dots, polymers and magnetofluorescent nanoparticles (72-83).
  • nanotechnology and small molecule chemistry can facilitate development of a wide range of nanomaterials for biomedical applications as diagnostic and therapeutic agents.
  • Another promising technique developed based on nanotechnology is the nanodrug and/or gene delivery system.
  • This new technology provides greater potential for many applications, including anti-tumor therapy by targeted delivery of therapeutic agents to tumors.
  • Cancer treatment represents an enormous biomedical challenge for drug delivery.
  • the unique properties of cancer require the development of a multifunctional drug delivery system that can be efficiently manufactured to target subtle molecular alterations that distinguish a cancer cell from healthy cells in the body.
  • a nanoparticle-mediated drug delivery system can significantly eliminate drug or drug carrier side effects.
  • Novel Fenretinide derivatives and their activity The purposes of the present studies include: first, chemically synthesize small and defined libraries of Fenretinide conjugates and derivatives; second, identify active molecules by using biologically relevant assays; and third, using the principles of peptdomimetics and nanoscience, modify these compounds further for the purpose of improving bioavailability, stability and ability to cross the blood-brain barrier. These molecules were screened using well-established rhabdoid tumor preclinical models, developed at Albert Einstein College of Medicine, to identify more active modified Fenretinide derivatives.
  • the active moiety required for the biological activity of 4-HPR was identified herein by generating a set of substitution derivatives in the phenyl ring. Furthermore, novel compounds that retain the effectiveness to inhibit thabdoid tumor cells were herein identified using in vitro cell culture assays, in a high-throughput liquid-handler robotics. In addition, the principle of peptidomimetics was used to generate various 4-HPR derivatives and using these systems, identify peptidomimetic derivatives of 4-HPR that show improved efficacy in cell survival assays of rhabdoid tumor cells. Identifying the active moiety, and active substitution derivations of Fenretinides have provided methods to conjugate Fenretinide to nanoparticles.
  • 4-HPR derivatives were synthesized by changing the functional group in para and meta position of benzene ring systems. Iodo- and other halogen derivatives were obtained for combining radiotherapy with chemotherapy. Once the position required for retaining the biological activity was identified, the Retinoic acid backbone was then modified. In addition, peptidomimetic compounds were synthesized.
  • All-trans retinoic acid (ATRA) was purchased from Sigma Chemical Co.
  • Dry DMF was stored over 4-A sieves and degassed before use by bubbling nitrogen through it for at least Ih.
  • the other reagents and solvents were purchased from commercially available sources and used without further purification. All reactions were conducted under a N 2 atmosphere. The reactions were monitored using TLC (Whatman® PE SIL G/UV Fluorescence UV 254 ). All the products prepared were purified by flash column chromatography on silica gel grade 62 (60-200 mesh, 15 ⁇ A). Proton nuclear magnetic resonance ( 1 H-NMR) were recorded in CDCl 3 using a Bruker 300 MHz instrument.
  • Electrospray Ionization (ESI) mass spectra were determined on a ThermoFinnigan LCQ Classic ion trap mass spectrometer (Waltham, MA) in positive ionization mode.
  • ESI Electrospray Ionization
  • the reaction mixture was heated at reflux under N 2 atmosphere for 5hr. The mixture became a clear yellow solution. After cooling slowly to a few degree above room temperature, the solution was acidified with concentrated HCl. A white solid was formed and was filted, washed with water and dried to give as white solid, which was recrystallized from hot ethanol and washed with dry hexane to give acid 8 as white crystals (0.85g, 83%).
  • RTs Rhabdoid tumors
  • RTs are highly aggressive and mostly incurable pediatric malignancies that arise in brain, kidneys and soft tissues (27, 84). RTs most commonly occur in children younger than five years of age with a peak incidence between birth and three years of age (27). Irrespective of their location, all RTs are characterized by the presence of sheets or nests of rhabdoid cells and exhibit biallelic deletions and/or mutations in the INIl/hSNF5 gene, located at chromosome 22ql 1.2 (85-88).
  • RPMI 1640 supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 50 U/ml penicillin, and 50 ⁇ g/ml streptomycin at 37°C with 5% CO 2 and 95% humidified air.
  • 4-HPR Fluorinide
  • Fenretinide or its synthetic derivatives were reconstituted in 100% ethanol as a 10 mM solution and the aliquots were stored frozen at -80°C, protected from light.
  • Working solutions (50 ⁇ M or 200 ⁇ M) and serial dilutions were prepared by diluting the stock solution with culture medium, such that the concentration of ethanol was ⁇ 2% in all dilutions.
  • MTS Assays to test the activity of Fenretinide and its derivatives in inhibiting the survival of rhabdoid tumor growth. Aliquots of 8 x 10 3 MON cells were plated in 96- well microdilution plates. Twenty four hours after seeding, the cells were treated with serial dilutions of each drug.
  • each well was stained with 20 ⁇ l of MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium, inner salt] that was mixed 20:1 V/V in PMS (phenazine methosulphate, CellTiter 96® AQueous Non-Radioactive Cell Proliferation Assay Kit, Promega, Madison, WI) added to each of the well in the microtiter plate containing 100 ⁇ l of culture medium.
  • MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium, inner salt
  • IC50 values were calculated using the nonlinear regression curve fit with sigmoidal dose response (variable slope) function. Relative IC50 is defined as the concentration giving a response exactly half way between the fitted top and bottom of the survival curve when graphed as percent inhibition versus the log of the concentration of compound. The fitting error, or standard error describes the error involved in fitting the curve.
  • IC 50 concentration the concentration of drug required to kill 50% of cells.
  • the peptidomimetic compound 11a exhibited similar cytotoxicity profile as compared to 4-HPR at lower concentrations of the drugs tested. However, the compounds 1 Ia and 1 Ig precipitated in cell culture medium and therefore, the exact IC50 value for these compounds could not be determined.
  • Compounds l ie, Hf, and 8 exhibited IC50 values of 47.18 ⁇ M, 29.06 ⁇ M, and >50 ⁇ M respectively, which are much greater than the parent compounds.
  • Two compounds with chloro- and flouro- substitutions at the meta-position of the phenyl group (compounds l ib and l ie respectively), exhibited similar level of activities to that of the parent 4-HPR compound (IC50 values of 10-13 ⁇ M, respectively).
  • compound Hd with substitution of an iodo-moiety at the meta- position of the phenyl ring demonstrated improved efficacy with IC50 reduced to 3 ⁇ M. This compound did not show any precipitation in the culture conditions.
  • Rhabdoid tumors arise due to loss of INIl tumor suppressor. INIl directly represses Cyclin Dl and rhabdoid tumors areakily dependent on Cyclin Dl for genesis, indicating that targeting the Cyclin/cdk axis is an effective novel strategy against these tumors. Since, rhabdoid tumors are extremely sensitive to Cyclin Dl, the ability of fenretinide derivatives to down-modulate Cyclin Dl was determined.
  • Figures 3 and 4 indicate the induction of cell cycle arrest and apoptosis by the different compounds.
  • Tables 5 and 6 show data illustrating the effects on cell cycle and apoptosis induction when MON cells were exposed to different compounds.
  • Figure 5 shows the effect of fenretinide, its derivatives and peptidomimetic compounds on expression of Cyclin Dl.
  • Table 5 Data illustrating the effect on cell cycle and apoptosis induction when MON cells were exposed for 2 days to halogen derivative of Fenretinide. A. Percentage of cells at various stages of cell cycle (Gl, S and G2) is indicated. B. Percentage of MON cells at sub- G 1 .
  • Table 6 Data illustrating the effect on cell cycle and apoptosis induction when MON cells w ⁇ exposed for 2 days to peptidomimetic derivative of Fenretinide. A. Percentage of cells at varic stages of cell cycle (Gl, S and G2) is indicated. B. Percentage of MON cells at sub-Gi
  • 4-HPR is a synthetic retinamide that has promising anticancer activity and minimal toxicity in humans.
  • the active moeity of 4-HPR required for its cytotoxic activity on rhabdoid cells was identified.
  • substitution of para-hydroxy group with halogens, nitro, methoxy, hydroxmethyl or hydroxyethyl groups abolished cytotoxic activity.
  • ortho- and meta- positions can be substituted, for example, with halogens or hydroxy groups. Substitution of halogens at the meta-position retained the cytotoxic activity, with iodo-substituions exhibiting better IC50 values than parent 4-HPR.
  • the iodo-derivative compounds 5(j) and l l(d) are more active when compared to parent Fenretinide and other derivative compounds, indicating that these compounds can be used for: (i) combining radiotherapy with chemotherapy by labeling with 1-131; and (ii) biodistribution studies by labeling with 1-124 by combining it with PET imaging.
  • the flouro derivative compound, 5(h) can be synthesized with Fl 8 isotope and can be used as an imaging agent. This molecule can be tested to determine if it is taken up by various tissues and tumors, by combining with PET studies.
  • Njar VC Gediya L
  • Purushottamachar P et al. Retinoic acid metabolism blocking agents (RAMBAs) for treatment of cancer and dermatological diseases.
  • RAMBAs Retinoic acid metabolism blocking agents
  • van Steensel MA Emerging drugs for ichthyosis. Expert Opin Emerg Drugs 2007;12:647-56.

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  • Dispersion Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne des dérivés peptidomimétiques synthétiques et des dérivés du groupe phényle de fenrétinide (4-HPR), ainsi que leurs utilisations comme agents thérapeutiques, de diagnostic et d'imagerie pour le traitement du cancer et d'autres maladies.
PCT/US2009/001538 2008-03-12 2009-03-11 Dérivés de fenrétinide et leurs utilisations comme agents thérapeutiques, de diagnostic et d'imagerie WO2009114136A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/735,544 US8460635B2 (en) 2008-03-12 2009-03-11 Fenretinide derivatives and uses thereof as therapeutic, diagnostic and imaging agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6905008P 2008-03-12 2008-03-12
US61/069,050 2008-03-12

Publications (2)

Publication Number Publication Date
WO2009114136A2 true WO2009114136A2 (fr) 2009-09-17
WO2009114136A3 WO2009114136A3 (fr) 2016-03-31

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US (1) US8460635B2 (fr)
WO (1) WO2009114136A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016011535A1 (fr) 2014-07-25 2016-01-28 Laurent Pharmaceuticals Formulation orale solide de fenrétinide
US10406127B2 (en) 2014-07-25 2019-09-10 Laurent Pharmaceuticals Solid oral formulation of fenretinide
US11007160B2 (en) 2013-04-16 2021-05-18 Monash University Method of viral inhibition

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8581005B2 (en) * 2009-04-13 2013-11-12 Albert Einstein College Of Medicine Of Yeshiva University Mitochondrial inhibitors to treat human disease

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4532343A (en) * 1982-11-19 1985-07-30 Sri International Aromatic retinoic acid analogues
US6696606B2 (en) * 2001-07-06 2004-02-24 The Ohio State University Research Foundation Solid phase synthesis of arylretinamides
US7169813B2 (en) * 2004-03-18 2007-01-30 Fondazione IRCCS “Istituto Nazionale Dei Tumori” 4-oxo-fenretinide, administered alone and in combination with fenretinide, as preventive and therapeutic agent for cancer
EP2277516A1 (fr) * 2004-06-23 2011-01-26 ReVision Therapeutics, Inc. Dérivés de rétinyle pour le traitement de troubles ophtalmiques
US20100183504A1 (en) * 2007-06-14 2010-07-22 Fanqing Frank Chen Multimodal imaging probes for in vivo targeted and non-targeted imaging and therapeutics

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11007160B2 (en) 2013-04-16 2021-05-18 Monash University Method of viral inhibition
US11752116B2 (en) 2013-04-16 2023-09-12 Monash University Method of viral inhibition
WO2016011535A1 (fr) 2014-07-25 2016-01-28 Laurent Pharmaceuticals Formulation orale solide de fenrétinide
US10406127B2 (en) 2014-07-25 2019-09-10 Laurent Pharmaceuticals Solid oral formulation of fenretinide
US10512619B2 (en) 2014-07-25 2019-12-24 Laurent Pharmaceuticals Solid oral formulation of fenretinide

Also Published As

Publication number Publication date
WO2009114136A3 (fr) 2016-03-31
US8460635B2 (en) 2013-06-11
US20110091383A1 (en) 2011-04-21

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